Necrotizing enterocolitis (NEC) is a leading cause of death and disability in premature infants. Patients that develop NEC do so suddenly and without warning, and upon surgical exploration of the abdomen, frequently demonstrate large regions of the intestine that are either dead or dying. In over half the cases, patients that develop NEC do not survive their disease, and in survivors, an additional third will develop long term complications related to the initial development of the disease. Currently, there is no specific therapy for NEC, and treatment involves the administration of broad spectrum antibiotics and surgical removal of the dead or dying intestine. Clearly, novel therapeutic approaches to this devastating disease are urgently needed.
In seeking to understand the pathogenesis of NEC, as well as to define novel therapeutic approaches for this disease, it was found that NEC is characterized by impaired enterocyte migration along the crypt-villus axis. The impaired enterocyte migration results in persistent mucosal defects, bacterial translocation, and the development of systemic sepsis which leads to death in many cases. In seeking to define the mechanisms that regulate enterocyte migration in both mice and humans, it was found that enterocytes migrate together as sheets, and that enterocyte migration is dependent upon intact inter-enterocyte communication via Cx43-mediated gap junctions (1, 2). Furthermore, the release of the pro-inflammatory cytokine interferon gamma (IFNγ) plays a critical role in the impairment of mucosal healing in part by inhibiting gap junctions between enterocytes (1, 2).
In other studies, it has been shown that human inflammatory bowel disease (“IBD”) is associated with impaired gap junctions within the intestinal mucosa (1, 2). Enterocyte migration is impaired in IBD just as it is in NEC.
Gap junctions are intercellular channels that exist between adjacent cells which allow the transfer of small molecules between adjoining cells. Each gap junction channel is comprised of a pair of hexameric arrays of individual subunits called connexins, of which the most widely expressed isoform is connexin-43 (Cx43; 2, 3, 4). The function of gap junctions is regulated in part through phosphorylation of the individual connexin molecules, which serves to regulate the localization of the channels at the plasma membrane as well as to regulate the channel through gating (5, 6).